Our studies conducted in the last year on obsessive-compulsive disorder (OCD) have had a primary focus on investigations of the mechanisms which may mediate successful treatment of the disorder by serotonergic (5-HT) agents including clomipramine, fluoxetine, and buspirone. Investigations conducted here and elsewhere have conclusively shown that clomipramine is more effective than structurally similar tricyclics such as desipramine, imipramine, and amitriptyline, all of which our less selective for serotonin. However, in a controlled comparison to clomipramine conducted here, the serotonin agonist buspirone was found to have similar efficacy in the treatment of OCD. In addition, our group conducted the first double-blind comparison of clomipramine versus fluoxetine in the treatment of OCD and demonstrated similar efficacy in both a randomized and non-randomized cohort of patients. This apparent preferential response to 5-HT selective agents in OCD is in contrast to the treatment response demonstrated In other anxiety and depressive disorders which fail to show a preferential response to serotonin-selective agents and represents further evidence of the importance of serotonergic pathways in OCD. In preliminary studies further evaluating possible serotonergic contributions to therapeutic effects in OCD, brief coadministration of the serotonin agonist, m-chlorophenylpiperazine (M-CPP), during chronic clomipramine and fluoxetine treatment led to a relative attenuation of the behavioral responses elicited by m-CPP prior to medication treatment in a group of OCD patients.